This section is intended to introduce various aspects of the art, which may be associated with exemplary embodiments of the present disclosure. This discussion is believed to assist in providing a framework to facilitate a better understanding of particular aspects of the present disclosure. Accordingly, it should be understood that this section should be read in this light, and not necessarily as admissions of prior art.
There are many applications related to transdermal and topical drug delivery (e.g., see, D. I. J. Morrow et al., “Innovative Strategies for Enhancing Topical and Transdermal Drug Delivery,” The Open Drug Delivery Journal, 2007, vol. 1, pp. 36-59). A good example is the external oxygen supply in the hyperbaric process (e.g., see “Diabetic Foot Ulcer Treatment Using Hyperbaric Oxygen Therapy Guide,” published by Sechrist Industries, Inc., copyright 2008). Human skin acts as a protective barrier, which keeps noxious substances out of the body and inhibits excessive loss of water from the internal organs. Nevertheless, strategies have been developed to deliver drugs to the skin and surpass the skin's barrier properties.
For example, it is known that carbon dioxide, when it is able to penetrate through the skin, has a positive effect of expanding blood vessels and thus naturally improving blood flow (known as The Bohr Effect). This effect has been observed numerous times when bathing in carbonated springs with high concentrations of carbon dioxide (e.g., see N. Nishimura et al., “Effects of repeated carbon dioxide-rich water bathing on core temperature, cutaneous blood flow and thermal sensation,” Eur. J. Appl. Physiol., vol. 87, pp. 337-342, Jun. 7, 2002).
It has been demonstrated that a cutaneous uptake of atmospheric oxygen contributes significantly to oxygen supply to the human dermis and epidermis. Oxygen can be supplied in such a manner to the upper skin layers at depths of 0.25 mm to 0.4 mm.
Based on the example above, one can come to a conclusion that a cutaneous external application of gasses (such as oxygen, carbon dioxide, ozone, etc.) can have very positive effects on the health of human beings in the same way as transdermal drug delivery. An important factor in such a drug delivery method is the permeability through the skin (e.g., see R. J. Scheuplein, “Permeability of the Skin: A Review of Major Concepts and Some New Developments,” The Journal of Investigative Dermatology, vol. 67, no. 5, pp. 672-676, 1976).
If one wants to use a cutaneous external application of gasses, one needs to find ways to provide penetration enhancers for the specific gasses utilized such that an optimal transdermal delivery can be achieved.
Gas nanobubbles for which the radius is less than 500 nm, have peculiar properties that if supplied cutaneously and externally to the human skin have a high probability of permeability through the skin, which may be further enhanced by physical and chemical enhancers that are applied in transdermal drug delivery (e.g., see, T. Higuchi, “Physical Chemical Analysis of Percutaneous Absorption Process from Creams and Ointments,” Journal of the Society of Cosmetic Chemists, pp. 85-97, 1959).
Nanobubbles are defined as gas-filled cavities in a solution (e.g., a water solution) with each of the nanobubbles having a diameter of less than 500 nm. Nanobubbles possess some peculiar properties such as minimal to no buoyancy effects, the nanobubble gas/liquid interface is negatively charged, due to their charge nanobubbles repel each other, nanobubbles avoid coalescence and dissipation, nanobubbles are stable in liquid (e.g, for at least several days), gas nanobubbles in a liquid contribute increased concentration of the dissolved gas in the liquid, gas nanobubbles (when properly generated) exhibit a very high density within the liquid carrier (e.g., 108-109 bubbles/mL), and due to their nano-diameter the nanobubbles have a very large interfacial area.
Based on a publication by Martin Chaplin (see, http://www1.lsbu.ac.uk/water/martin_chaplin.html), the approximate ranges of bubble generation are as presented in FIG. 4, which illustrates the density of microbubbles and nanobubbles in liquid as a function of their generated size. As one can observe, microbubbles are defined in the range of 10 μm to 100 μm in diameter (with a central density of approximately 104 to 106 bubbles/mL), while nanobubbles are defined in the range of less than 1 μm, and primarily less than 500 nm (with a density of approximately between 108 and 109 nanobubbles/mL).
Using simple calculations as well as what is demonstrated in FIG. 4, if one generates bubbles that are smaller in diameter than 500 nm the concentration of the nanobubbles should be on the order of 108 to 109 nanobubbles/mL. On the other hand, if the bubbles concentration is on the order of 104 to 106 bubbles/mL, the expected diameter of the bubbles is approximately 10 μm, which are microbubbles by definition. Basically, if one claims that his generator creates nanobubbles, then the measured concentration in a liquid should be around 108 nanobubbles or higher.